The invention disclosed herein generally relates to a composition of matter used in the treatment of wounds, a method of making same, and a method of using same.
There have been many different substances and methods developed in the past for treating wounds, depending upon the type and location and severity of the wound. A wound is generally defined as an injury to an area of the body of a human or animal. Although injury to the surface of the skin is the most well known type of wound, the surfaces of internal organs may also be wounded, such as during surgery, rupture of the spleen or liver, or resulting from traumatic blows to the body surface in the vicinity of an internal organ.
Medical practice characterizes wounds as chronic or acute, according to the persistency and severity of the wound. A chronic wound is one that is prolonged or lingering, rather than promptly healed. An acute wound is one that occurs relatively quickly, and heals relatively quickly as well. Tissue wounds may have a wide spectrum of manifestations, as small as merely an abnormal microscopic tear or fissure in tissue (or a surface thereof), or as large as the abrasion or ablation of the skin covering a substantial portion of the body, such as in a burn victim. Acute wounds covering a large or movable surface are usually the most difficult to guard from infection, and to heal.
The invention described herein is primarily related to substances topically applied to the exterior surface of chronic wounds, although the invention described herein also has some applications for facilitating the healing of other wounds such as acute wounds. The composition of matter described herein is especially suited to topical application to burn wounds and chronic lesions, such as ulcers on the feet of diabetics. However, the compositions of matter and the methods described herein are not limited solely to that topical application.
Wound healing is affected by the presence of various substances found in the blood and bodily fluids. The blood is the primary medium for delivering healing agents to the wound site, and for transporting foreign or harmful substances away from the wound. Whole blood is primarily comprised of three main types of cells suspended in a protein rich solution known as plasma.
The three main cell types of whole blood are erythrocytes (a.k.a. red blood cells), leukocytes (a.k.a. white blood cells) and thrombocytes (a.k.a. platelets). The red blood cells are the iron-containing cells that facilitate the transport and transfer of oxygen to body tissue, and the removal of carbon dioxide. The white blood cells perform functions such as phagocytosis of foreign bodies and production of antibodies, primarily responsible for fighting infection and foreign substances within the blood or wound site. Platelets perform many functions such as plugging leaks in blood vessels and helping begin the process leading to the formation of a blood clot; platelets contain substances known as growth factors that facilitate the formation of new tissue.
Although there are several methods for separating whole blood into its various components, one of the most convenient and expeditious methods is accomplished by differentially centrifuging blood or some of its components (i.e., apheresis). In this way, the red and white blood cells and plasma may be separated out and returned to the donor's or patient's body, leaving the sequestered platelets in essentially concentrated form for use in wound healing techniques. From blood extracted from a patient, the platelets may thus be obtained and activated for use on the same patient; methods of using a patient's own blood are called "autologous" or "autogenic" donor methods. Methods using blood donated by one or more third parties for use by a patient are called "homologous" or "heterologous" donor methods, or collectively called "allogenic" methods.
One of the proteins suspended in plasma is fibrinogen, which reacts with substances released into (or attracted by) wound sites to produce sticky strands offibrin. Such reactions result in the cross linking of the strands to form a mesh that holds and supports the deposit or growth of other tissue materials at the wound site.
The wound healing process is generally considered to occur in several stages, generally know as the healing cascade. After tissue injury, platelets are among the first cells to appear in the vicinity of the wound. Activation of a platelet by an agonist such as thrombin, or other agonists such as those listed elsewhere herein, leads to the release of granule material from within the platelet. Such granulation activation results in the release of proteins known as growth factors, primarily concentrated in the alpha granules of platelets. These released growth factors stimulate the formation of new tissue; when applied to wounds, growth factors have been known to increase the rate of collagen laydown, vascular ingrowth, fibroblast proliferation and overall healing. The release of a protein known as platelet-derived growth factor (PDGF) is a chemotactic for monocytes, neutrophils and fibroblasts into the wound, to begin the inflammatory stage of the healing process. During this time, monocytes secrete PDGF and another platelet protein known as transforming growth factor-.beta.1, which recruits and activates fibroblagts, a prerursor to fibrinogen, to begin the repair stage of the healing process. Subsequently, wound healing continues through the process of collagen remodeling within the wound.
The presence of growth factors promotes wound healing. The invention described herein increases the amount of growth factors in the wound, and thereby facilitates the promotion of the healing rate. This may be especially important in "wounded" patients, especially those with chronic wounds who may lack sufficient circulation to facilitate the healing cascade. The invention described herein also facilitates the covering of the wound area with a substance that prevents or helps to reduce infection caused by most bacteria; and to the extent that the wound treatment material is made from autologous blood or similar biological materials, the invention described herein reduces the risks associated with the use of treatment materials made from biological materials obtained from one or more third parties. An autologous product avoids some of the common problems associated with the use of biological materials from third parties, such as (for example) screening to assure that the donor was biologically or immunologicaly compatible with the patient, and otherwise free of hepatitis, HIV and the like.
Base upon the foregoing general scientific principles, already known in the field are wound sealants made from biological materials obtained primarily from tissue other than blood platelets. For example, wound sealants include "fibrin glue," which often is essentially a mixture of co-coagulants (thrombin and calcium), concentrated fibrinogen and other coagulation proteins. In most applications, the primary roles of fibrin glue are to seal wound surfaces to prevent loss of blood and other body fluids after surgery, and to provide adhesion between adjacent tissue surfaces. These products form a hard, cast-like covering over the area to be sealed, and tend to be non-yielding to limb movement.
The production of fibrin glue often requires obtaining fibrinogen from blood through a process known as cryoprecipitation, including both freeze-thaw cycles and relatively lengthy centrifuigation of plasma in controlled environments, to concentrate the fibrinogen in large enough amounts required for use; the precipitant thus obtained is frozen to -20.degree. to -30.degree. centigrade before storage. These requirements make such materials unsuitable for application during the course of surgery, especially emergency surgery without an hour or more lead time; moreover, to the extent this process depends upon the use of autologous biological materials, using this process shortly before or during surgery may result in the loss of crucial bodily fluids during a time when the patient's body is badly in need of such fluids. By contrast, substantially larger amounts of concentrated platelets can be more conveniently obtained within a matter of minutes from more recent methods of differential blood centrifugation not requiring freezing, without significant loss of bodily fluids.
To date, there has been much research concerning fibrin glue. This is considered to be a separate field from the present invention, primarily because fibrin glues typically contain cryoprecipitated proteins without platelets. The use of fibrin glue is discussed extensively in the scientific literature; for example, see the references cited in U.S. Pat. No. 5,585,007 issued to Antanavich et al on Dec. 17, 1996.
One method of differential centrifiugation essentially allows separating the patient's own blood into at least three different components: packed erythrocytes (red blood cells), plasma and platelet concentrate. Platelet concentrate can be combined with a solution of either sodium or calcium mixed with thrombin ("calcified thrombin"), often to form a gelatinous composition of activated platelets that, when made with the necessary viscosity, can be utilized as a wound sealant. Such sealants typically set up into a hard mass covering the application site, thereby sealing the site. The initially sticky, gelatinous state usually hardens to serve the functions of (1) stopping the loss of blood and other bodily fluids, because it effectively acts as a patch; (2) sealing wounds against external contaminants; and (3) preventing traditional problems associated with the mere stitching of wounds.
Wound healing compositions including platelets have advantages over materials without platelets. One reason is that natural wound healing agents are released by the platelets. Further, the concentration of platelets likewise allows for a concentrated amount of wound healing factors. Additionally, to the extent that the wound healing composition is made from the biological materials of the patient, the risks associated with heterologous donors (such as disease, immunologic reactions, or the like) are eliminated.
The work surrounding the field of autologous platelet gel to date has focused on perioperative blood treatment (hemostatic effect)--preventing loss of blood during or immediately following surgery. Normally, when a patient is on the operating table, the patient will lose large amounts of blood and other bodily fluids, depending upon the type of surgery involved. To counter this blood loss, the traditional approach is to infuse the patient with blood, which is usually donated from one or more third parties (or sometimes donated by the patient in anticipation of surgical needs). There exists many different types of methods for collecting blood that are normally used in this type situation.
Because there is obviously an increased risk of disease, immunologic reaction, or other complications associated with procedures including heterologous blood donation, recent efforts have been made to use blood contemporaneously obtained from the patient during surgery. This blood can be fractionated and/or filtered, and subsequently re-infused into the patient, saving much time, expense, bodily fluids and avoiding normal risks discussed above.
It is from the perioperative blood treatment arena that the uses for autologous platelet gel were focused. The use of platelet gel on open wounds resulting from surgery have recently met great success. This particular use allows the patient to keep his/her own blood and also reduce costs.
The following patents are arguably related to the invention disclosed herein:
Patent Number Inventor Date 5,733,545 Hood March 31, 1998 5,585,007 Antanavich, et al. December 17, 1996 5,165,938 Knighton November 24, 1992 5,674,912 Martin October 7, 1997
However, the inventions disclosed therein are patentably distinct from the invention disclosed herein.
The Hood patent claims a plasma-buffy coat concentrate comprising plasma, platelets (at a concentration of at least 10.sup.9 cells/ml), fibrinogen (at a concentration of at least 5 mg/ml), and white blood cells (at a concentration of at least 3 times 10.sup.7 cells/ml). The Hood invention achieves hemoconcentration by removal of water from plasma. The Hood invention also fails to recognize the benefits of increased levels of vitamins, antibiotics and other substances. For instance, higher amounts of vitamin C is believed to prolong the viscosity and longevity of a gelatinous composition of fibrinous matter derived substantially from platelets. As another example, the Hood invention fails to recognize the benefits of including retinoids, such as vitamin A (retinol) and/or vitamin E. For instance, patients undergoing treatment including steroids often have immune systems that are suppressed, or otherwise non-responsive to stimuli; increased amounts of vitamin A are known to counteract that non-responsiveness, and thereby facilitate the promotion of wound healing. Similarly, increasing the level of vitamin E is believed to facilitate the promotion of wound healing.
The Knighton patent discloses the use of isolated multiple growth factors combined with a biologically compatible carrier substance, after sequestration (and removal) of all platelet membranes and plasma containing fibrin from the growth factor exudate prepared. Discarding such membranes essentially removes from the composition residual growth factors known to be concentrated in the membranes, and potential receptor sites for facilitating matrix formation. The method utilized in Knighton also requires a number of time consuming and labor intensive steps, including storage at -20.degree. to -30.degree. centigrade prior to use. The Knighton method also requires that wound treatments be repeated on a daily basis.
The Antanavich patent discloses a composition based primarily on plasma and, like Knighton, requires a biologically acceptable carrier for administering a plasma concentrate comprising platelets, fibrinogen and fibrinectin. The Antanavich composition is essentially a fibrin glue meant to have a high tensile strength (viscosity), sufficient to seal a wound.
To the extent that the Martin patent is relevant, Martin discloses a composition comprising a sunscreen agent, an anti-inflammatory agent, and a wound healing composition. (Martin, column 6 line 66 through column 7 line 2.) Said wound healing composition comprises the combination of pyruvate, an anti-oxidant (including vitamins A, C and E), and fatty acids required for repairing cellular membranes. (Martin, column 7 lines 2 through 8.) The utility and function of said vitamins to the Martin composition, intended for use in sunlight rather than shielded from sunlight, are distinctly different from the utility and function of the vitamins to the invention disclosed herein, as explained hereinbelow.
The chemical reactions and cascades that normally happen when thrombin is added to the concentrated platelets are indeed complex. They are discussed in the scientific article by Reeder, et al, in Proceedings of the American Academy of Cardiovascular Perfusion, Vol. 14, January 1993. Adding a preservative, or healing promotion materials that do not detract from, substantially interfere with, or even destroy these different reactions is the crux of the invention disclosed herein.
One object of the invention is to provide a wound treatment material that is capable of quick and convenient production in the presence of the patient.
Another object of the invention is to provide a wound treatment material that facilitates the promotion of wound healing.
Another object is to provide a wound treatment material that facilitates the prevention of wound infection.
Another object is to provide a method of making a wound treatment material satisfying the objectives expressed, implied or inherent herein.
Another object is to provide a method of using a wound treatment material satisfying the objectives expressed, implied or inherent herein.